3-46858425-A-T

Position:

• chr3-46858425-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The ENST00000292327.6(MYL3):​c.518T>A​(p.Met173Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M173T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYL3 ENST00000292327.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.89

Genes affected

MYL3 (HGNC:7584): (myosin light chain 3) MYL3 encodes myosin light chain 3, an alkali light chain also referred to in the literature as both the ventricular isoform and the slow skeletal muscle isoform. Mutations in MYL3 have been identified as a cause of mid-left ventricular chamber type hypertrophic cardiomyopathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a chain Myosin light chain 3 (size 193) in uniprot entity MYL3_HUMAN there are 36 pathogenic changes around while only 6 benign (86%) in ENST00000292327.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-46858425-A-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 3-46858425-A-T is Pathogenic according to our data. Variant chr3-46858425-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181449.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYL3	NM_000258.3	c.518T>A	p.Met173Lys	missense_variant	5/7	ENST00000292327.6	NP_000249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYL3	ENST00000292327.6	c.518T>A	p.Met173Lys	missense_variant	5/7	1	NM_000258.3	ENSP00000292327	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 01, 2011

The Met173Lys mutation in the MYL3 gene has not been reported previously as a disease causing mutation or as a benign polymorphism, to our knowledge. However, another mutation affecting this same codon (Met173Val) has been reported in a patient with childhood onset HCM and it was absent from more than 1,000 control alleles (Morita et al. 2008). Met173Lys results in a non conservative amino acid substitution of a non polar Methionine with a polar Lysine at a position that is conserved throughout evolution. Furthermore, Met173Lys was not observed in up to 200 control alleles from individuals of Caucasian ancestry tested at GeneDx, indicating it is not a common benign polymorphism in this population. Mutations in MYL3 are rare in HCM, and have been reported in only about 1% of patients with an autosomal dominant familial form of the disease (Cirino A et al., 2011). The variant is found in HCM panel(s). -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 23, 2022

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 181449). This variant has not been reported in the literature in individuals affected with MYL3-related conditions. This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 173 of the MYL3 protein (p.Met173Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.83	P;P
Vest4		0.92
MutPred		0.55		Gain of ubiquitination at M173 (P = 0.0131);Gain of ubiquitination at M173 (P = 0.0131);
MVP		0.96
MPC		1.3
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.94
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730880962; hg19: chr3-46899915;